Abstract for TER90007

Developmental Toxicity of Methacrylamide in CD-1 Swiss Mice

Abstract

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings may not have been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. For more information, see the Explanation of Levels of Evidence for Developmental Toxicity. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.

This study was conducted to assess the potential for orally administered methacrylamide to cause developmental toxicity. The oral route of administration corresponds to the potentially most hazardous human route of exposure to MAC. The CD-1 mouse was selected as the test animal for this study based on evidence for MAC-induced toxicity in other strains/stocks of mouse in the literature, and to correspond with other teratology and reproductive toxicity studies of the parent compound and congeners sponsored by the National Toxicology Program.

Methacrylamide (MAC, CAS No. 79-39-0) was administered by gavage to timed-pregnant Swiss (CD-1 ) mice (15-30/group) on gestational days 6-17 at dose levels of 0, 30, 60, 120, or 180 mg/kg body weight/day. Animals were observed daily for clinical signs of toxicity. Food and water consumption and body weights were determined on gd 0, 3, 6, 9, 12, 15, and 17. All animals were killed on gd 17 and examined for maternal body weight, implant status, fetal weight, sex, and morphological development. After evaluation of Replicate I data, the 30 mg/kg/day dose group was eliminated, since both the 30 and 60 mg/kg/day dose groups caused no effect.

Maternal body weights did not differ significantly between the control group and any of the MAC-treated groups on gd 0 through 15. On gd 17, however, maternal body weight was significantly depressed at 180 mg/kg/day . Maternal weight gain during treatment and gestation were also reduced at the high dose, although corrected maternal weight gain was unaffected. Relative (g/kg body weight/day) food intake exhibited a significant increasing trend for the interval gd 12 to 15. Relative water consumption was not significantly affected. No signs of neurotoxicity were observed.

One maternal animal in each of the 0, 120, and 180 mg/kg/day MAC groups died of indeterminant causes during the course of the study. On gd 17, animals from the 120 and 180 mg/kg/day MAC-exposed groups had significantly increased relative, but not absolute, liver weights when compared to control animals. In addition, gravid uterine weight was decreased at the high dose, compared to the control group.

Fetal examination on gd 17 showed no effects of MAC on preimplantation loss. The percent nonlive implants per litter was significantly increased at 180 mg/kg/day MAC, whereas the number of litters with nonlive implants exhibited a significant dose-related increasing trend. Similarly, the percent adversely affected implants per litter exhibited a significant increasing trend. These effects were due primarily to an increase in resorptions per litter. Three dams in the high dose group had totally resorbed litters, compared to none in the other treatment groups. The number of live fetuses per litter was unaffected by treatment. However, mean fetal body weight exhibited a decreasing trend, and was significantly decreased in the mid- and high-dose groups, 7 and 15%, respectively, when compared to the control mean. Examination of the fetuses for external, visceral and skeletal malformations did not reveal any significant differences from controls.

In summary, 60 mg/kg/day MAC was a no-observed-adverse-effect-level for both maternal and developmental toxicity. The mid-dose (120 mg/kg/day MAC) produced slight maternal effects, and clear evidence of developmental toxicity, observed as a decrease in mean fetal body weight per litter. The high dose (180 mg/kg/day MAC) produced mild maternal effects, observed as an increase in relative liver weight, and clear evidence of developmental toxicity, observed as an increased proportion of nonlive implants per litter, and decreased mean fetal body weight per litter. The fetal effects seen in this study were evident at exposure levels that resulted in only slight maternal effects.